Tuberculosis remains one of the most significant global health problems today, as it has for centuries. Although the development of chemotherapeutic agents for treating tuberculosis resulted in a dramatic decline in the incidence of tuberculosis from the 1950's until the 1980's, especially in developed countries, the disease has not been contained and is increasing throughout the world. Approximately one third of the world's population is infected with Mycobacterium tuberculosis and three million people die of tuberculosis annually. An alternative approach to chemotherapy for control of infectious diseases has been the development of vaccines against specific components of pathogens or toxins produced by the pathogens. An effective vaccine against tuberculosis would afford long-lasting protection to individuals without having to rely on chemotherapy. Protection of large segments of populations at risk of infection would decrease the incidence of tuberculosis and contribute to reducing spread of disease, even to those who are immunocompromised and for whom a vaccine may be ineffective. The long-term goal is to construct a vaccine that would protect human populations against tuberculosis. We propose to identify surface protein antigens of M. tuberculosis that elicit protective immune responses against the tubercle bacilli. The genes specifying such antigens will be cloned into avirulent Salmonella-vaccine strains, which will be used to immunize mice to evaluate the types of responses elicited by the cloned antigens. The objective during the Phase II study will be to evaluate the best candidate antigens expressed by recombinant avirulent Salmonella vaccine strains for their abilities to protect mice and humans against infection by M. tuberculosis. PROPOSED COMMERCIAL APPLICATION: Recombinant avirulent Salmonella vaccines against M. tuberculosis would be useful worldwide in preventing tuberculosis. Because of increased frequency of travel among nearly all populations of the world and because of the infectious nature of M. tuberculosis, the incidence of TB will continue to increase and chemotherapy has been unable to contain the disease. Therefore, an effective vaccine against TB would have significant commercial value.